Novel variants in CDH2 are associated with a new syndrome including Peters anomaly

Abstract

Peters anomaly (PA) is a congenital corneal opacity associated with corneo‐lenticular attachments. PA can be isolated or part of a syndrome with most cases remaining genetically unsolved. Exome sequencing of a trio with syndromic PA and 145 additional unexplained probands with developmental ocular conditions identified a de novo splicing and three novel missense heterozygous CDH2 variants affecting the extracellular cadherin domains in four individuals with PA. Syndromic anomalies were seen in three individuals and included left‐sided cardiac lesions, dysmorphic facial features, and decreasing height percentiles; brain magnetic resonance imaging identified agenesis of the corpus callosum and hypoplasia of the inferior cerebellar vermis. CDH2 encodes for N‐cadherin, a transmembrane protein that mediates cell‐cell adhesion in multiple tissues. Immunostaining in mouse embryonic eyes confirmed N‐cadherin is present in the lens stalk at the time of separation from the future cornea and in the developing lens and corneal endothelium at later stages, supporting a possible role in PA. Previous studies in animal models have noted the importance of Cdh2/cdh2 in the development of the eye, heart, brain, and skeletal structures, also consistent with the patient features presented here. Examination of CDH2 in additional patients with PA is indicated to confirm this association.

First evidence of SOX2 mutations in Peters' anomaly: Lessons from molecular screening of 95 patients

“…Two patients ( P4 , P83 ) had 22q11.2 deletion syndrome (arr[GRCh38]22q11.2(22:19022279_21098156)x1). Although PA has rarely been described in patients with 22q11.2 deletion, it might be a frequent cause of PA. Reis et al 18 pointed out the role of TBX1 in both, the retinoic acid pathway (critical to OD) and the PITX2 pathway.…”

“…What our work also shows is that most of the genes associated with PA were known before the advent of next-generation sequencing. 2,18 Its development has however allowed the simultaneous exploration of multiple genes tied to ocular malformations and thereby widened the phenotypic spectrum of the previously known diseasecausing genes. These latter include SOX2, not previously linked to PA, but which we demonstrated here to be associated with PA condition.…”

“…Copy number variations (CNVs), such as the 22q11.2 microdeletion, have also been reported in individuals with syndromic PA 17 . Despite the number of genes known to play a role in PA, previous studies have only reached genetic diagnoses for 1/4 of patients 18,19 …”

“…16 Copy number variations (CNVs), such as the 22q11.2 microdeletion, have also been reported in individuals with syndromic PA. 17 Despite the number of genes known to play a role in PA, previous studies have only reached genetic diagnoses for 1/4 of patients. 18,19 Thus, this study first sought to determine the contribution of each OD gene in an exceptional cohort of 95 unrelated patients affected by syndromic and non-syndromic PA. Accordingly, we performed array comparative genomic hybridization (aCGH), whole genome, exome or targeted sequencing (TS) in the largest genotyped PA cohort ever reported.…”

Cadherin 2-Related Arrhythmogenic Cardiomyopathy

“…34 Another multisystemic disorder recently associated to genetic variants in CDH2 is the Peters anomaly, mainly characterized by corneal abnormalities. 35 The reason why some CDH2 variants may create these multisystemic disorders while others result in a pure ACM phenotype is currently unknown; further studies are needed to unravel the functional effect of specific CDH2 variants and the molecular mechanisms leading from cadherin 2 dysfunction to different phenotypes.…”